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Method for manufacture of escitalopram

Active Publication Date: 2009-03-12
H LUNDBECK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

[0005]It has now been found that resolution of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile by fractional crystallization of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile as a salt with (+)—(S,S)— or (−)—(R,R)—O,O′-di-p-toluoyl-tartaric acid in a solvent system comprising 1-propanol wherein not more than 0.5 mol (+)—(S,S)— or (−)—(R,R)—O,O′-di-p-toluoyl-tartaric acid is used per mol 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile results in a crystalline product wherein the crystals are larger and of a different shape than those from 2-propanol. This process has proven to be a robust and stable method for producing crystals with good filtering properties. This results in much better draining properties and reduced filtration times which have an important impact on large scale production. Typical filtration times for an industrial scale batch is a few hours or less.

Problems solved by technology

Insufficient removal of the mother liquors gives a product with a low enantiomeric purity and therefore additional purifications are required.
Purifications are time and solvent consuming.
These problems are more evident on an industrial scale.

Method used

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  • Method for manufacture of escitalopram

Examples

Experimental program
Comparison scheme
Effect test

experiment 1

[0046

[0047](+)—O,O′-Di-p-toluoyl-(S,S)-tartaric acid (0.39 eq) was dissolved in 1-propanol (3.44 V). The mixture was heated up to ca. 40° C. and acetic acid (0.2 eq.) was added. This solution was transferred within one hour to a solution of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base in 1-propanol (0.95 V) containing 0.1 V of toluene. The resolution mixture, containing now in total 4.4 V 1-propanol was seeded with seed crystals comprising S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile and (+)—O,O′-di-p-toluoyl-(S,S)-tartaric acid and then stirred at 40° C. for 2 hours. The mixture was cooled to 20-25° C. within 2 hours. The product was filtered and washed twice with 1-propanol. The enantiomeric purity was typically in the range from about 91% to about 98% S.

[0048]The product was re-slurried in 1-propanol (2.5 V) at around 50° C. for 2 hours. The mixture was cooled to 20-25° C. The produc...

experiment 2

[0050

[0051](+)—O,O′-Di-p-toluoyl-(S,S)-tartaric acid (0.4 eq) was dissolved in 1-propanol (3.5 V). The mixture was heated up to ca. 40° C., acetic acid (0.2 eq.) was added and then the solution is transferred to a solution of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile free base in 1-propanol containing 0.1 V toluene. The resolution mixture, containing now in total 4.5 V 1-propanol was seeded with seed crystals comprising S-4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile and (+)—O,O′-di-p-toluoyl-(S,S)-tartaric acid and then stirred at 40° C. for two hours. The mixture was cooled to 20-25° C. in two hours. The product was filtered (filter reactor) and washed with 1-propanol.

[0052]The enantiomeric purity was typically around 97% S or higher.

[0053]An exemplary batch gave molar yield: 33.8%, enantiomeric purity: 99.0% S.

experiment 3

[0054

[0055]The general procedure of Experiment 2 was applied, however 0.5 eq of (+)—O,O′-di-p-toluoyl-(S,S)-tartaric acid and 10V of 1-propanol were used. No toluene or acetic acid was present in the system.

[0056]An exemplary batch gave molar yield: 29.5%; enantiomeric purity: 99.2% S.

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Abstract

This patent discloses a method for resolution of 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile as a racemic or non-racemic enantiomer mixture into its isolated enantiomers, said method comprising the step of fractionally crystallizing 4-[4-(dimethylamino)-1-(4′-fluoro-phenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile as a salt with the (+)—(S,S)— or (−)—(R,R)-enantiomer of O,O′-di-p-toluoyl-tartaric acid in a solvent system comprising 1-propanol, ethanol or acetonitrile.

Description

TECHNICAL FIELD OF THE INVENTION[0001]The present invention relates to a method for manufacture of the well-known anti-depressant escitalopram.BACKGROUND OF THE INVENTION[0002]Escitalopram is a well-known antidepressant drug that has the following structure:[0003]It is a selective, centrally active serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitor, accordingly having antidepressant activities.[0004]Escitalopram and the pharmaceutical activity thereof are disclosed in U.S. Pat. No. 4,943,590. Two methods for preparation of escitalopram are disclosed. In one of them 4-[4-(dimethylamino)-1-(4′-fluorophenyl)-1-hydroxybutyl]-3-(hydroxymethyl)-benzonitrile is fractionally crystallized as a salt with (+)—O,O′-di-p-toluoyl-(S,S)-tartaric acid in 2-propanol. The crystalline product produced in this way consists of small crystals that drain very slowly and tend to retain the mother liquors. Insufficient removal of the mother liquors gives a product with a low enantiomeric purity and th...

Claims

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Application Information

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IPC IPC(8): C07D307/87C07C209/86
CPCC07C253/34C07D307/87C07C255/59
Inventor DE FAVERI, CARLAHUBER, FLORIAN ANTON MARTINDANCER, ROBERT
Owner H LUNDBECK AS
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